Fused bicyclic compounds for the treatment of disease

ABSTRACT

Described herein are fused bicyclic compounds, compositions, and methods for their use for the treatment of disease.

BACKGROUND OF THE INVENTION

Famesoid X receptor (FXR) is a member of the nuclear hormone receptorsuperfamily of ligand-activated transcription factors. Bile acids areFXR physiological ligands. On activation by bile acids, FXR regulates awide variety of target genes that are critically involved in the controlof bile acid, lipid and glucose homeostasis. Thus, FXR plays a key rolein the pathogenesis of cholestatic diseases, non-alcoholic fatty liverdisease and inflammatory bowel disease.

SUMMARY OF THE INVENTION

Described herein are compounds of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa), pharmaceutical compositions that include such compounds, andmethods of use thereof, for modulating FXR. In one aspect is theadministration of at least one FXR modulator described herein to amammal in the treatment of diseases, disorders or conditions that wouldbenefit from FXR modulation.

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl).

In another aspect provided herein is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl).

In one embodiment is a compound of Formula (I) or (II) wherein R⁶ and R⁷are hydrogen. In a further embodiment is a compound of Formula (I) or(II) wherein R⁴ and R⁵ are each independently optionally substitutedC₁-C₆alkyl. In a further embodiment is a compound of Formula (I) or (II)wherein R⁴ and R⁵ are methyl. In yet a further embodiment is a compoundof Formula (I) or (II) wherein R³ is —C(O)R²⁰. In another embodiment isa compound of Formula (I) or (II) wherein R³ is —S(O)₂R²⁰. In anotherembodiment is a compound of Formula (I) or (II) wherein R²⁰ isoptionally substituted aryl. In another embodiment is a compound ofFormula (I) or (II) wherein R²⁰ is optionally substitutedC₃-C₈cycloalkyl. In another embodiment is a compound of Formula (I) or(II) wherein R²⁰ is optionally substituted C₂-C₉heterocycloalkyl. Inanother embodiment is a compound of Formula (I) or (II) wherein R³ is—C(O)N(R²¹)R²². In another embodiment is a compound of Formula (I) or(II) wherein R²¹ is hydrogen and R²² is optionally substituted aryl. Ina further embodiment is a compound of Formula (I) or (II) wherein R²¹ ishydrogen and R²² is optionally substituted aryl. In another embodimentis a compound of Formula (I) or (II) wherein R⁸ is —C(O)OR²⁵. In anotherembodiment is a compound of Formula (I) or (II) wherein R²⁵ isoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (I) or (II) wherein R²⁵ is methyl. In another embodiment is acompound of Formula (I) or (II) wherein R²⁵ is ethyl. In a furtherembodiment is a compound of Formula (I) or (II) wherein R² is hydrogen.In a further embodiment is a compound of Formula (I) or (II) wherein R¹is hydrogen. In another embodiment is a compound of Formula (I) or (II)wherein R¹ is C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, oroptionally substituted C₂-C₆alkynyl. In another embodiment is a compoundof Formula (I) or (II) wherein R¹ is C₁-C₆alkyl. In another embodimentis a compound of Formula (I) or (II) wherein R¹ is —CF₃.

In another aspect provided herein is a compound of Formula (III), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (III) wherein R³⁰ is F. Inanother embodiment is a compound of Formula (III) wherein n is 1. Inanother embodiment is a compound of Formula (III) wherein R³¹ ishalogen. In another embodiment is a compound of Formula (III) whereinR³¹ is F. In another embodiment is a compound of Formula (III) whereinR⁴ and R⁵ are each —CH₃.

In a further embodiment, provided herein is a compound having thestructure of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof:

In another aspect provided herein is a compound of Formula (IV), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally-   substituted C₃-C₈cycloalkyl, optionally substituted    C₂-C₉heterocycloalkyl, aryl, or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (IV) wherein R³⁰ is F. Inanother embodiment is a compound of Formula (IV) wherein n is 1. Inanother embodiment is a compound of Formula (IV) wherein R³¹ is halogen.In another embodiment is a compound of Formula (IV) wherein R³¹ is F. Inanother embodiment is a compound of Formula (IV) wherein R⁴ and R⁵ areeach —CH₃.

In a further embodiment, provided herein is a compound having thestructure of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof:

In another aspect provided herein is a compound of Formula (V), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl:-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (V) wherein R³⁰ is F. Inanother embodiment is a compound of Formula (V) wherein n is 1. Inanother embodiment is a compound of Formula (V) wherein R³¹ is halogen.In another embodiment is a compound of Formula (V) wherein R³¹ is F. Inanother embodiment is a compound of Formula (V) wherein R⁴ and R⁵ areeach —CH₃.

In a further embodiment, provided herein is a compound having thestructure of Formula (Va), or a pharmaceutically acceptable salt orsolvate thereof:

In another aspect provided herein is a compound of Formula (VI), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl:-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (VI) wherein R³⁰ is F. Inanother embodiment is a compound of Formula (VI) wherein n is 1. Inanother embodiment is a compound of Formula (VI) wherein R³¹ is halogen.In another embodiment is a compound of Formula (VI) wherein R³¹ is F. Inanother embodiment is a compound of Formula (VI) wherein R⁴ and R⁵ areeach —CH₃.

In a further embodiment, provided herein is a compound having thestructure of Formula (VIa), or a pharmaceutically acceptable salt orsolvate thereof:

In a further embodiment is a compound of Formula (III), (IIIa), (IV),(IVa), (V), (Va), (VI) or (VIa) wherein R¹ is hydrogen. In anotherembodiment is a compound of Formula (III), (IIIa), (IV), (IVa), (V),(Va), (VI) or (VIa) wherein R¹ is optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (III), (IIIa), (IV), (IVa),(V), (Va), (VI) or (VIa) wherein R¹ is —CF₃. In another embodiment is acompound of Formula (III), (IIIa), (IV), (IVa), (V), (Va), (VI) or (VIa)wherein R¹ is unsubstituted C₁-C₆alkyl.

In another aspect provided herein is a compound of Formula (IX), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxyl, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₈cycloalkyl ring or an optionally substituted    C₂-C₉heterocycloalkyl ring;-   R⁶ and R⁷ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In another aspect provided herein is a compound of Formula (X), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₈cycloalkyl ring or an optionally substituted    C₂-C₉heterocycloalkyl ring;-   R⁶ and R⁷ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein R⁶ and R⁷are hydrogen. In a further embodiment is a compound of Formula (IX) or(X), or a pharmaceutically acceptable salt or solvate thereof, whereinR⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein R⁴ and R⁵are methyl. In another embodiment is a compound of Formula (IX) or (X),or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is—C(O)OR²⁵. In another embodiment is a compound of Formula (IX) or (X),or a pharmaceutically acceptable salt or solvate thereof, wherein R⁸ is—C(O)OR²⁵ and R²⁵ is optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IX) or (X), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R⁸ is —C(O)OR²⁵ and R²⁵ ismethyl. In another embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein —C(O)OR²⁵and R²⁵ is ethyl. In another embodiment is a compound of Formula (IX) or(X), or a pharmaceutically acceptable salt or solvate thereof, whereinR⁸ is —C(O)OR²⁵ and R²⁵ is isopropyl. In another embodiment is acompound of Formula (IX) or (X), or a pharmaceutically acceptable saltor solvate thereof, wherein R⁸ is —C(O)N(R²⁵)R²⁶. In another embodimentis a compound of Formula (IX) or (X), or a pharmaceutically acceptablesalt or solvate thereof, wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently selected from the group consisting of hydrogenand optionally substituted C₁-C₆alkyl. In a further embodiment is acompound of Formula (IX) or (X), or a pharmaceutically acceptable saltor solvate thereof, wherein R² is hydrogen. In a further embodiment is acompound of Formula (IX) or (X), or a pharmaceutically acceptable saltor solvate thereof, wherein R¹ is hydrogen. In another embodiment is acompound of Formula (IX) or (X), or a pharmaceutically acceptable saltor solvate thereof, wherein R¹ is optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein R¹ is —CF₃.In another embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein R¹ isunsubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IX) or (X), or a pharmaceutically acceptable salt or solvate thereof,wherein R³⁰ is halogen. In another embodiment is a compound of Formula(IX) or (X), or a pharmaceutically acceptable salt or solvate thereof,wherein R³⁰ is F. In another embodiment is a compound of Formula (IX) or(X), or a pharmaceutically acceptable salt or solvate thereof, whereinR³⁰ is optionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl).In another embodiment is a compound of Formula (IX) or (X), or apharmaceutically acceptable salt or solvate thereof, wherein R³⁰ isunsubstituted —(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl). In anotherembodiment is a compound of Formula (IX) or (X), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In anotherembodiment is a compound of Formula (IX) or (X), or a pharmaceuticallyacceptable salt or solvate thereof, wherein R³⁰ is unsubstituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In another embodiment is acompound of Formula (IX) or (X), or a pharmaceutically acceptable saltor solvate thereof, wherein n is 1. In another embodiment is a compoundof Formula (IX) or (X), or a pharmaceutically acceptable salt or solvatethereof, wherein R³¹ is halogen. In another embodiment is a compound ofFormula (IX) or (X), or a pharmaceutically acceptable salt or solvatethereof, wherein R³¹ is F. In another embodiment is a compound ofFormula (IX) or (X), or a pharmaceutically acceptable salt or solvatethereof, wherein n is 0.

Any combination of the groups described above or below for the variousvariables is contemplated herein. Throughout the specification, groupsand substituents thereof are chosen by one skilled in the field toprovide stable moieties and compounds.

In another aspect, provided herein is a pharmaceutical compositioncomprising a compound of Formula (I), (II), (III), (IIIa), (IV), (IVa),(V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable diluent, excipient or binder. In oneembodiment, the pharmaceutical composition comprising the compound ofFormula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa),(VII), (VIII), (IX), (IXa), (X), or (Xa), or a pharmaceuticallyacceptable salt or solvate thereof, is formulated for a route ofadministration selected from oral administration, parenteraladministration, buccal administration, nasal administration, topicaladministration, or rectal administration.

In another aspect is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering to the mammal a compound of Formula (I), (II), (III),(IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa),(X), or (Xa), or a pharmaceutically acceptable salt or solvate thereof.

In a further embodiment is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadministering to the mammal a compound of Formula (I), (II), (III),(IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa),(X), or (Xa), or a pharmaceutically acceptable salt or solvate thereof;wherein the disease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis or obesity. In anotherembodiment is the use of a compound of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa) in the manufacture of a medicament for the treatment of a disease,disorder, or condition that would benefit from FXR modulation. Inanother embodiment is the use of a FXR modulator in the manufacture of amedicament for use in the treatment of a disease, disorder or conditionin a mammal, wherein the disease, disorder or condition in a mammal isnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis or obesity.

In another aspect is a method of modulating FXR activity comprisingcontacting FXR, or portion thereof, with a compound of Formula (I),(II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII),(IX), (IXa), (X), or (Xa), or a pharmaceutically acceptable salt orsolvate thereof.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The Famesoid X receptor (FXR; also referred to as NR1H4; nuclearreceptor nomenclature committee 1999) is a member of the steroid andthyroid hormone nuclear receptor superfamily of ligand regulatedtranscription factors. FXR is highly expressed in the liver, kidney,intestines and the adrenals and at lower levels in the vasculature(Forman et al., Cell 1995, 81(5):687-93). Bile acids, the end-productsof cholesterol catabolism, bind directly to the ligand binding pocket ofFXR and act as agonists to increase the receptor's ability to activatetranscription (Makishima et al., Science 1999, 284(5418): 1362-5 1999;Mi et al., Mol Cell 2003, 11(4): 1093-100; Parks et al., Science 1999,284(5418):1365-8; Wang et al., Mol Cell 1999, 3(5):543-53). In responseto bile acid binding FXR regulates a network of genes that control thesynthesis, transport, and catabolism of bile acids, but alsotriglycerides and cholesterol (Chawla et al., Cell 2000, 103(1): 1-4;Repa and Mangelsdorf, Annu Rev Cell Dev Biol 2000, 16:459-81). Thus FXRfunctions as a regulator of lipid metabolism by modifying geneexpression in response to quantitative changes in the metabolism andbreakdown of cholesterol. In support of this conclusion, studies inhumans and in animals have demonstrated that modifying bile acid levelscan have profound effects on plasma triglyceride and cholesterol levels(Angelin et al., J Lipid Res 1978, 19(8): 1017-24; Bateson et al., Br JClin Pharmacol 1978, 5(3):249-54; Iserand Sali, Drugs 1981,21(2):90-119; Kuroki et al., Lipids 1999, 34(8):817-23).

Metabolic disease including obesity, diabetes, hypertension, andcardiovascular disease, are diseases driven by both mulitfactorialgenetics (thrifty genotypes) as well as lifestyle habits, and are nowreaching epidemic proportions in developed nations. It is believed thatincreasingly high caloric diets combined with sedentary life styles aremajor contributors to the growing incidence of these diseases.Importantly hyperlipidemia is associated with many types of metabolicdisease, and statistics from the American Heart Association indicatethat approximately half of the adult population in the United States hasplasma cholesterol levels that put individuals at risk for thedevelopment of cardiovascular disease (American Heart Association, Heartdisease and stroke statistics—2005 update; 2005:1-59). Furthermore, theThird Report of the National Cholesterol Education Program Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III; ATPIII, National CholesterolEducation Program 2001) has identified elevated triglyceride levels asan independent risk factor for the development of cardiovasculardisease. Approximately one third of the adult population in the UnitedStates that have elevated cholesterol levels also have increasedtriglycerides. The elevation in plasma triglycerides has now beenrecognized as an early and dominant dyslipidemic symptom in patientswith obesity, metabolic syndrome and diabetes and has been suggested toplay a causative role in the development of insulin resistance and typeII diabetes (Hegarty et al., Acta Physiol Scand 2003; 178(4):373-83;Shulman, J Clin Invest 2000; 106(2): 171-6).

Current standard of care for hyperlipidemia focuses on lowering lowdensity lipoprotein cholesterol (LDL) using the statin class ofhydroxymethy-glutaryl-CoA reductase inhibitors (National CholesterolEducation Program 2001). However, even after statin therapy asignificant number of patients still exhibit elevated levels of plasmatriglycerides and triglyceride-rich lipoproteins including very lowdensity lipoproteins (VLDL) and intermediate density lipoproteins (IDL)(Friday, Exp Biol Med (Maywood) 2003, 228(7):769-78; Quilliam et al., JManag Care Pharm 2004, 10(3):244-50). To treat this population ofpatients with concurrent high plasma triglyceride levels the ATPIII hasidentified lowering of triglyceride-rich cholesterol fractions(VLDL+IDL) as a secondary target of drug therapy (National CholesterolEducation Program 2001). Unfortunately treatment of such patients withfibrates, an approved class of triglyceride lowering drugs, haspotential adverse side effects, including the possibility of increasedLDL cholesterol as well as carrying the risk of fatal rhabdomyolysis, sothat combination therapy must proceed cautiously (National CholesterolEducation Program 2001). Similarly nicotinic acid, a second approvedtriglyceride lowering agent, is contraindicated in patients with insulinresistance and type II diabetes (Capuzzi et al., Curr Atheroscler Rep2000, 2(1):64-71). Taken together these observations highlight the needfor an effective therapeutic agent for the lowering of triglycerides andnon-HDL cholesterol in patients with cardiovascular disease, diabetes,and metabolic syndrome.

The maintenance of lipid homeostasis requires coordinate control ofcholesterol and triglyceride synthesis, transport, up-take, andexcretion. Interestingly, studies in human and in animal models haveuncovered a link between bile acids, the metabolic end-product ofcholesterol metabolism, and lipid homeostasis. Clinical studies in thelate 1970s exploring the effect of bile acids on cholesterol gallstonesdemonstrated that treatment with chenodeoxycholic acid (CDCA) reducesplasma triglyceride levels (Bateson et al., Br J Clin Pharmacol 1978,5(3):249-54; Iser and Sali, Drugs 1981, 21(2):90-119). In contrast,treatment with bile acid sequestrants, which deplete intestinal bileacids, increase triglycerides (Angelin et al., J Lipid Res 1978; 19(8):1017-24). Importantly the bile acid-dependent decrease in triglyceridesis mediated, at least in part, through a reduction in the production ofVLDL (Hirokane et al., J Biol Chem 2004, 279(44):45685-92; Post et al.,Arterioscler Thromb Vase Biol 2004, 24(4):768-74; Sirvent et al., FEBSLett 2004, 566(1-3): 173-7; Kang and Davis, Biochim Biophys Acta 2000,1529(1-3):223-30). While bile acids are known to mediate the absorptionof cholesterol and fat in the intestine the mechanistic basis for theconnection between bile acids and lipid levels remained unclear untilthe recent characterization of FXR.

The FXR was originally cloned and classified as an orphan member of thenuclear hormone receptor superfamily based upon DNA sequence homology.Initial studies identified famesol as a ligand for FXR (Forman et al.,Cell 1995, 81(5):687-93), however, subsequent analysis demonstrated thatbile acids bind directly to the ligand binding domain of FXR andfunction as activators of the receptor's transcriptional activity. Thebinding affinities of bile acids for FXR is near the concentration thatthese compounds reach in animals (μM) lending support to the idea thatbile acids function as endogenous ligands in vivo (Makishima et al.,Science 1999, 284(5418):1362-5 1999; Mi et al., Mol Cell 2003, 11(4):1093-100; Parks et al., Science 1999, 284(5418):1365-8; Wang et al., MolCell 1999, 3(5):543-53). Activation of FXR upon bile acid binding leadsto transcriptional down-regulation of cholesterol 7α-hydroxylase(CYP7A1), the rate limiting enzyme in the conversion of cholesterol tobile acids. Inhibition of CYP7A1 by bile acids occurs via FXR-dependentinduction of the small heterodimeric partner (SHP; also referred to asNR0B2, Nuclear Receptor Nomenclature Committee 1999), a transcriptionalrepressor. Binding sites for FXR have been identified in the SHPpromoter indicating that this gene is a direct target of FXR (Lu et al.,Mol Cell 2000, 6(3):507-15; Goodwin et al., Mol Cell 2000, 6(3):517-26).Thus bile acid-dependent repression of CYP7A1 is indirect and resultsfrom a transcriptional cascade initiated by FXR. A similar SHP-dependentmechanism has been described for the bile acid repression of anothergene involved in bile acid synthesis, CYP8B1 (sterol 12a hydroxylase;Yang et al., Biochim Biophys Acta 2002, 1583(1):63-73), and for thesodium/taurocholate cotransporter peptide (NTCP) which is one of twomajor transporters responsible for bile acid up-take by the liver(Denson et al., Gastroenterology 2001; 121(1): 140-7). In contrast thegenes encoding the bile salt export pump (BSEP) and the multidrugresistance protein 2 (MDR2) are directly induced by FXR, once again viabinding sites in their respective promoter regions (Ananthanarayanan etal., J Biol Chem 2001, 276(31):28857-65; Huang et al, J Biol Chem 2003,278(51):51085-90; Liu et al, J Clin Invest 2003, 112(11): 1678-87).These two transporters are required for the transfer of bile acids(BSEP) and phospholipids (MDR2) out of the hepatocytes into the biliarysystem. This pattern of FXR-dependent gene expression defines a classicfeedback loop where high levels of bile acids inhibit new bile acidsynthesis and bile acid uptake while simultaneously promoting their ownclearance.

The regulation of bile acid synthesis and transport by FXR has importantimplications for cholesterol metabolism. Repression of CYP7A1 and CYP8B1impacts the bile acid synthetic pathway at two important points. First,inhibition of CYP7A1, the rate limiting enzyme, can decrease synthesisand reduce the size of the bile acid pool. Second, inhibition of CYP8B1alters bile acid composition by favoring the production of morehydrophilic bile acids such as CDCA (muricholic acid/MCA in mice)(Russell, Annu Rev Biochem 2003, 72:137-74). Importantly, studies inmice have demonstrated that the more hydrophilic bile acids are lessefficient at promoting intestinal cholesterol absorption (Wang et al.,Am J Physiol Gastrointest Liver Physiol 2003, 285(3):G494-502).

Although regulating bile acid synthesis may contribute to theFXR-dependent effects on lipid metabolism, gene expression analysisindicates that FXR also directly influences triglyceride synthesis andVLDL production. FXR agonists induce the genes encoding fibroblastgrowth factor 19 (Holt et al., Genes Dev 2003, 17(13): 1581-91),acylation stimulating protein (a proteolytic product of complement C3;Li et al., J Biol Chem 2005, 280(9):7427-34), apolipoprotein CII (Kastet al., Mol Endocrinol 2001, 15(10): 1720-8), and apolipoprotein AV(Prieur et al., J Biol Chem 2003, 278(28):25468-80) all of which areknown to promote the clearance and oxidation of fat carried bytriglyceride rich lipoproteins. Additionally FXR inhibits expression ofthe genes encoding apolipoprotein CIII (Claudel et al., Gastroenterology2003, 125(2):544-55), an inhibitor of lipoprotein lipase, and the sterolresponse element binding protein 1c (SREBP1c; Watanabe et al., J ClinInvest 2004, 113(10): 1408-18). SREBP1c, a member of basichelix-loop-helix family of transcription factors, functions as a mastertranscriptional regulator of the enzymes required for fatty acidsynthesis (Osborne, J Biol Chem 2000, 275(42):32379-82). Taken togetherthe genetic network controlled by FXR defines a signal transductionsystem poised to respond to changes in fat and carbohydrate dietaryintake-driven lipid homeostasis. High levels of cholesterol in the liverwill lead to increased production of bile acids and subsequentactivation of FXR. In response to this activating signal FXR decreasesthe absorption of cholesterol in the intestine, favoring excretion,increases the clearance and oxidation of triglycerides and decreases thesynthesis of fatty acids leading to a reduction in VLDL production.

The ability of FXR to regulate bile-acid synthesis, clearance andhomeostasis as supported by the ability of FXR ligands to promote thetransport of bile acid and phospholipids out of the liver suggests autility for such compounds in diseases of disturbed bile acid andcholesterol flow such as Primary Biliary cirrhosis and NASH. In thisregard FXR agonists have been shown to be effective in animal models ofcholestasis, gallstones, and liver fibrosis (Liu et al., J Clin Invest2003, 112(11): 1678-87; Fiorocci et al., Gastroenterology 2004, 127(5):1497-512; Fiorocci et al., J Pharmacol Exp Ther 2005, 313(2):604-12;Fiorocci et al., J Pharmacol Exp Ther 2005, 314(2):584-95).

In some embodiments, compounds disclosed herein are used in thetreatment of a disease, disorder or condition in a mammal that wouldbenefit from FXR modulation.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is selected from nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis and obesity. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH). In some embodiments, is a method of treating adisease, disorder or condition in a mammal that would benefit from FXRmodulation comprising adminstering a compound of Formula (I), (II),(III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder or condition in a mammal ishyperlipidemia. In some embodiments, is a method of treating a disease,disorder or condition in a mammal that would benefit from FXR modulationcomprising adminstering a compound of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is hypercholesterolemia.In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is hypertriglyceridemia. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is dyslipidemia. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is lipodystrophy. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is atherosclerosis. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is atherosclerotic disease.In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is atheroscleroticcardiovascular disease. In some embodiments, is a method of treating adisease, disorder or condition in a mammal that would benefit from FXRmodulation comprising adminstering a compound of Formula (I), (II),(III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa), or a pharmaceutically acceptable salt or solvatethereof, wherein the disease, disorder or condition in a mammal isSyndrome X. In some embodiments, is a method of treating a disease,disorder or condition in a mammal that would benefit from FXR modulationcomprising adminstering a compound of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa), or a pharmaceutically acceptable salt or solvate thereof, whereinthe disease, disorder or condition in a mammal is diabetes mellitus. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is type II diabetes. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is insulin insensitivity. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from FXR modulation comprisingadminstering a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa),or a pharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is hyperglycemia. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is cholestasis. In someembodiments, is a method of treating a disease, disorder or condition ina mammal that would benefit from FXR modulation comprising adminsteringa compound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), or apharmaceutically acceptable salt or solvate thereof, wherein thedisease, disorder or condition in a mammal is obesity.

In some embodiments, is a method of modulating FXR activity comprisingcontacting FXR, or portion thereof, with a compound of Formula (I),(II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII),(IX), (IXa), (X), or (Xa), or a pharmaceutically acceptable salt orsolvate thereof. In some embodiments, the compound of Formula (I), (II),(III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa), or a pharmaceutically acceptable salt or solvatethereof, is an FXR agonist. In some embodiments, the compound of Formula(I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII),(VIII), (IX), (IXa), (X), or (Xa), or a pharmaceutically acceptable saltor solvate thereof, is an FXR partial agonist.

In some embodiments, the disease, disorder or condition in a mammal thatwould benefit from FXR modulation is selected from nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis and obesity.

Compounds

In one aspect, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl).

In one embodiment is a compound of Formula (I) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (I) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (I) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (I) wherein R⁴ and R⁵ are each methyl.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (I) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(I) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (I) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (I) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl. R³ is—C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl. R³ is—S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (I) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (I) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted heteroaryl. In another embodiment is a compound of Formula(I) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substituted aryl.In another embodiment is a compound of Formula (I) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (I) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (I) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are methyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (I) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (I) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (I) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (I) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (I) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R¹ is—OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (I) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (I) wherein R¹ is—OR¹⁰ and R¹⁰ is methyl.

In another aspect, provided herein is a compound of Formula (II), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₆alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₆alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₆alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₆alkylene)-(heteroaryl).

In one embodiment is a compound of Formula (II) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (II) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (II) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (II) wherein R⁴ and R⁵ are each methyl.

In another embodiment is a compound of Formula (II) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (II) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(II) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (II) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (II) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (II) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (II) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment is a compound of Formula (II) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ isoptionally substituted heteroaryl.

In another embodiment is a compound of Formula (II) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (II)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (II) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (II)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (II) wherein R⁶ andR⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (II) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R² is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (II) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (II) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (II) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (II) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (II) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ is—OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (II) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (II) wherein R¹ is—OR¹⁰ and R¹⁰ is methyl.

In yet another aspect, provided herein is a compound having thestructure of Formula (III), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (III) wherein n is 0. Inanother embodiment is a compound of Formula (III) wherein n is 1. Inanother embodiment is a compound of Formula (III) wherein n is 2. Inanother embodiment is a compound of Formula (III) wherein n is 3. Inanother embodiment is a compound of Formula (III) wherein n is 4.

In another embodiment is a compound of Formula (III) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (III) wherein n is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (III) wherein n is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(III) wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkyl amine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (III) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(III) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (III) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (III) wherein n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (III) wherein n is 1 and R³¹is F.

In another embodiment is a compound of Formula (III) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (III) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (III)wherein R³⁰ is F, n is 1 and R³¹ is F.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R⁴ and R⁵ are each methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(III) wherein R⁴ and R⁵ are each ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (III) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (III) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R¹ ismethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (III) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (III) wherein R¹ is optionally substitutedC₂-C₆alkynyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (III) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In a further embodiment of the aforementioned embodiments is a compoundof Formula (III) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (III) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (III) wherein R²⁵ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (III) wherein R²⁵ isethyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (IIIa), or a pharmaceutically acceptable salt orsolvate thereof:

In some embodiments is a compound of Formula (IIIa) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (IIIa) wherein R¹is halogen. In some embodiments is a compound of Formula (IIIa) whereinR¹ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (IIIa) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In some embodiments is a compound of Formula (IIIa)wherein R¹ is optionally substituted C₂-C₆alkynyl. In some embodimentsis a compound of Formula (IIIa) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In some embodiments is a compound of Formula (IIIa) wherein R¹ is —OR¹⁰and R¹⁰ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (IIIa) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IIIa) wherein R²⁵ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IIIa) wherein R²⁵is ethyl.

In yet another aspect, provided herein is a compound having thestructure of Formula (IV), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (IV) wherein n is 0. Inanother embodiment is a compound of Formula (IV) wherein n is 1. Inanother embodiment is a compound of Formula (IV) wherein n is 2. Inanother embodiment is a compound of Formula (IV) wherein n is 3. Inanother embodiment is a compound of Formula (IV) wherein n is 4.

In another embodiment is a compound of Formula (IV) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IV) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IV) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (IV)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IV) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IV) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IV) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (IV) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IV) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IV) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IV)wherein R³⁰ is F, n is 1 and R³¹ is F.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R⁴ and R⁵ are each methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IV) wherein R⁴ and R⁵ are each ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (IV) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (IV) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R¹ ismethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (IV) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IV) wherein R¹ is optionally substitutedC₂-C₆alkynyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IV) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IV) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆ alkyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IV) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. Ina further embodiment of the aforementioned embodiments is a compound ofFormula (IV) wherein R²⁵ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IV) wherein R²⁵ isethyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (IVa), or a pharmaceutically acceptable salt orsolvate thereof:

In some embodiments is a compound of Formula (IVa) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (IVa) wherein R¹is halogen. In some embodiments is a compound of Formula (IVa) whereinR¹ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (IVa) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In some embodiments is a compound of Formula (IVa) whereinR¹ is optionally substituted C₂-C₆alkynyl. In some embodiments is acompound of Formula (IVa) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. Insome embodiments is a compound of Formula (IVa) wherein R¹ is —OR¹⁰ andR¹⁰ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (IVa) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IVa) wherein R²⁵ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IVa) wherein R²⁵ isethyl.

In another aspect, provided herein is a compound having the structure ofFormula (V), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl:-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (V) wherein n is 0. Inanother embodiment is a compound of Formula (V) wherein n is 1. Inanother embodiment is a compound of Formula (V) wherein n is 2. Inanother embodiment is a compound of Formula (V) wherein n is 3. Inanother embodiment is a compound of Formula (V) wherein n is 4.

In another embodiment is a compound of Formula (V) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (V) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (V) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (V)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (V) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkyl amine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (V) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(V) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (V) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (V) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (V) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (V) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (V) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (V) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (V) wherein R³⁰ is F, n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (V) wherein R³⁰ is F, n is 1 and R³¹ ishalogen. In another embodiment is a compound of Formula (V) wherein R³⁰is F, n is 1 and R³¹ is F.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (V) wherein R⁴ and R⁵ are each methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(V) wherein R⁴ and R⁵ are each ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (V) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (V) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (V) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (V) wherein R¹ ismethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (V) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (V) wherein R¹ is optionally substitutedC₂-C₆alkynyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (V) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. Ina further embodiment of the aforementioned embodiments is a compound ofFormula (V) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (V) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (V) wherein R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (V) wherein R²⁵is hydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(V) wherein R²⁵ is hydrogen and R²⁶ is methyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (V) whereinR²⁵ is hydrogen and R²⁶ is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (V) wherein R²⁵ ishydrogen and R²⁶ is isopropyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (V) wherein R²⁵ andR²⁶ are each optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (V) whereinR²⁵ and R²⁶ are methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (V) wherein R²⁵ and R²⁶ are ethyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (Va), or a pharmaceutically acceptable salt orsolvate thereof:

In some embodiments is a compound of Formula (Va) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (Va) wherein R¹is halogen. In some embodiments is a compound of Formula (Va) wherein R¹is optionally substituted C₁-C₆alkyl. In some embodiments is a compoundof Formula (Va) wherein R¹ is optionally substituted C₂-C₆alkenyl. Insome embodiments is a compound of Formula (Va) wherein R¹ is optionallysubstituted C₂-C₆alkynyl. In some embodiments is a compound of Formula(Va) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. In some embodiments is acompound of Formula (Va) wherein R¹ is —OR¹⁰ and R¹⁰ is optionallysubstituted C₁-C₆alkyl. In some embodiments is a compound of Formula(Va) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Va) wherein R²⁵and R²⁶ are hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (Va) wherein R²⁵ is hydrogen andR²⁶ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Va) wherein R²⁵ ishydrogen and R²⁶ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Va) wherein R²⁵ ishydrogen and R²⁶ is ethyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Va) wherein R²⁵ is hydrogen andR²⁶ is isopropyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Va) wherein R²⁵ and R²⁶ are eachoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Va) wherein R²⁵ andR²⁶ are methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Va) wherein R²⁵ and R²⁶ are ethyl.

In yet another aspect, provided herein is a compound having thestructure of Formula (VI), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl:-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl;-   R³⁰ is halogen;-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkyl amine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (VI) wherein n is 0. Inanother embodiment is a compound of Formula (VI) wherein n is 1. Inanother embodiment is a compound of Formula (VI) wherein n is 2. Inanother embodiment is a compound of Formula (VI) wherein n is 3. Inanother embodiment is a compound of Formula (VI) wherein n is 4.

In another embodiment is a compound of Formula (VI) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (VI) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (VI) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (VI)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (VI) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkyl amine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (VI) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VI) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (VI) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (VI) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (VI) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (VI) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (VI) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (VI) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (VI) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (VI) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (VI)wherein R³⁰ is F, n is 1 and R³¹ is F.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VI) wherein R⁴ and R⁵ are each methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VI) wherein R⁴ and R⁵ are each ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VI) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (VI) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (VI) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VI) wherein R¹ ismethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (VI) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (VI) wherein R¹ is optionally substitutedC₂-C₆alkynyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (VI) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In a further embodiment of the aforementioned embodiments is a compoundof Formula (VI) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (VI) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VI) wherein R²⁵ and R²⁶ are hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (VI) whereinR²⁵ is hydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VI) wherein R²⁵ is hydrogen and R²⁶ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VI) wherein R²⁵ is hydrogen and R²⁶ is ethyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (VI) whereinR²⁵ is hydrogen and R²⁶ is isopropyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VI) wherein R²⁵ andR²⁶ are each optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (VI) whereinR²⁵ and R²⁶ are methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VI) wherein R²⁵ and R²⁶ are ethyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (VIa), or a pharmaceutically acceptable salt orsolvate thereof:

In some embodiments is a compound of Formula (VIa) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (VIa) wherein R¹is halogen. In some embodiments is a compound of Formula (VIa) whereinR¹ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (VIa) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In some embodiments is a compound of Formula (VIa) whereinR¹ is optionally substituted C₂-C₆alkynyl. In some embodiments is acompound of Formula (VIa) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. Insome embodiments is a compound of Formula (VIa) wherein R¹ is —OR¹⁰ andR¹⁰ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (VIa) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIa) wherein R²⁵ and R²⁶ are hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (VIa) whereinR²⁵ is hydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIa) wherein R²⁵ is hydrogen and R²⁶ is methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIa) wherein R²⁵ is hydrogen and R²⁶ is ethyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (VIa) whereinR²⁵ is hydrogen and R²⁶ is isopropyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIa) wherein R²⁵and R²⁶ are each optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIa) wherein R²⁵ and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIa) wherein R²⁵and R²⁶ are ethyl.

In another aspect, provided herein is a compound of Formula (VII), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); R¹¹ and R¹² are each independently    selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or optionally    R¹¹ and R¹² together with the nitrogen atom to which they are    attached, form an optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl).

In one embodiment is a compound of Formula (VII) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (VII) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VII) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (VII) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (VII) wherein R⁴ and R⁵ are each methyl.

In another embodiment is a compound of Formula (VII) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (VII) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VII) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VII) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (VII) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (VII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (VII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (VII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (VII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (VII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (VII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (VII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (VII) wherein R⁶and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is —C(O)OR²⁵. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, and optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (VII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (VII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (VII) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VII) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R⁸ is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VII) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VII) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VII) wherein R⁸is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VII) wherein R⁸is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R² is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VII) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VII) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VII) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₆alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₆alkylene)-(aryl), optionally substituted—(C₁-C₆alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (VII) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (VII) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R¹ is—OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (VII) wherein R¹ is —OR¹⁰ and R¹⁰is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VII) wherein R¹ is—OR¹⁰ and R¹⁰ is methyl.

In another aspect, provided herein is a compound of Formula (VIII), or apharmaceutically acceptable salt or solvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴, R⁵, R⁶, and R⁷ are each independently selected from the group    consisting of hydrogen, halogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, and optionally substituted    C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); R¹¹ and R¹² are each independently    selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or optionally    R¹¹ and R¹² together with the nitrogen atom to which they are    attached, form an optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₆alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₆alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl).

In one embodiment is a compound of Formula (VIII) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (VIII) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VIII) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (VIII) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (VIII) wherein R⁴ and R⁵ are each methyl.

In another embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (VIII) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(VIII) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (VIII)wherein R⁶ and R⁷ are each methyl. In another embodiment is a compoundof Formula (VIII) wherein R⁶ and R⁷ are each hydrogen.

In another embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl. In anotherembodiment is a compound of Formula (VIII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (VIII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl.R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl. Inanother embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment is a compound of Formula (VIII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl.

In another embodiment is a compound of Formula (VIII) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are independently optionally substitutedC₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment is a compound of Formula (VIII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl. R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted heteroaryl. In another embodiment is a compoundof Formula (VIII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment is a compound of Formula (VIII) wherein R⁶and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is —C(O)OR²⁵. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is —C(O)OR²⁵, and R²⁵ is independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is —C(O)OR²⁵, and R²⁵ is independently selected from the groupconsisting of hydrogen, and optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionallysubstituted C₁-C₆ alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (VIII)wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R⁸ is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are methyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (VIII) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (VIII) whereinR⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R² is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (VIII) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (VIII) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (VIII) wherein R¹ is halogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIII) wherein R¹ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIII) wherein R¹ is optionally substituted C₂-C₆alkenyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIII) wherein R¹ is optionally substituted C₂-C₆alkynyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(VIII) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (VIII)wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (VIII) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl.

In yet another aspect, provided herein is a compound having thestructure of Formula (IX), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆ alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    -(G-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxyl, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₈cycloalkyl ring or an optionally substituted    C₂-C₉heterocycloalkyl ring;-   R⁶ and R⁷ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (IX) wherein n is 0. Inanother embodiment is a compound of Formula (IX) wherein n is 1. Inanother embodiment is a compound of Formula (IX) wherein n is 2. Inanother embodiment is a compound of Formula (IX) wherein n is 3. Inanother embodiment is a compound of Formula (IX) wherein n is 4.

In another embodiment is a compound of Formula (IX) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IX) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (IX) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (IX)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IX) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IX) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2,and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IX) whereinR³⁰ is optionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl),n is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IX) wherein R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IX) whereinR³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ isindependently halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (IX)wherein R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IX) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IX) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (IX) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IX)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IX) wherein R³⁰ is optionally substituted—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IX) wherein R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (IX) wherein R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen.In another embodiment is a compound of Formula (IX) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is F.

In another embodiment is a compound of Formula (IX) wherein n is 0 andR³⁰ is halogen. In another embodiment is a compound of Formula (IX)wherein n is 0 and R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In another embodiment is acompound of Formula (IX) wherein n is 0 and R³⁰ is optionallysubstituted —O—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl).

In another embodiment is a compound of Formula (IX) wherein R⁴ and R⁵are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IX) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IX) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (IX) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (IX) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (IX) wherein R⁴ and R⁵ together with the carbonatom to which they are attached, form an optionally substitutedC₃-C₈cycloalkyl ring or an optionally substituted C₂-C₉heterocycloalkylring.

In another embodiment is a compound of Formula (IX) wherein R⁶ and R⁷are each independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IX) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IX) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IX) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (IX) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IX) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IX) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IX) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IX) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IX) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IX) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (IX) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (IX) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IX) wherein R⁸ is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IX) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R⁸ is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IX) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IX) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IX) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IX) wherein R² is optionallysubstituted C₁-C₆ alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IX) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IX) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IX) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IX) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (IX) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (IX) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R¹ is—OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (IX) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (IX) wherein R¹ is—OR¹⁰ and R¹⁰ is methyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (IXa), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted aryl,    optionally substituted heteroaryl, and —C(O)R¹⁴;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁴ is optionally substituted C₁-C₆alkyl:-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl;-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (IXa) wherein n is 0. Inanother embodiment is a compound of Formula (IXa) wherein n is 1. Inanother embodiment is a compound of Formula (IXa) wherein n is 2. Inanother embodiment is a compound of Formula (IXa) wherein n is 3. Inanother embodiment is a compound of Formula (IXa) wherein n is 4.

In another embodiment is a compound of Formula (IXa) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IXa) wherein n is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment is a compound of Formula (IXa) wherein n is 2 andeach R³¹ is halogen. In another embodiment is a compound of Formula(IXa) wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IXa) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(IXa) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2,and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (IXa) whereinR³⁰ is optionally substituted —(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl),n is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (IXa) wherein R³⁰ is optionally substituted—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —O—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), n is2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (IXa) whereinR³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ isindependently halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is optionallysubstituted —(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (IXa)wherein R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IXa) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IXa) wherein n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IXa) wherein n is 1 and R³¹is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (IXa)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxyl, optionally substitutedC₁-C₆alkyl amine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (IXa) wherein R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (IXa) wherein R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (IXa) wherein R³⁰ is optionally substituted—O—(C₂-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen.In another embodiment is a compound of Formula (IXa) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is F.

In another embodiment is a compound of Formula (IXa) wherein n is 0 andR³⁰ is halogen. In another embodiment is a compound of Formula (IXa)wherein n is 0 and R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In another embodiment is acompound of Formula (IXa) wherein n is 0 and R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl).

In some embodiments is a compound of Formula (IXa) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (IXa) wherein R¹is halogen. In some embodiments is a compound of Formula (IXa) whereinR¹ is optionally substituted C₁-C₆alkyl. In some embodiments is acompound of Formula (IXa) wherein R¹ is unsubstituted C₁-C₆alkyl. Insome embodiments is a compound of Formula (IXa) wherein R¹ is —CF₃. Insome embodiments is a compound of Formula (IXa) wherein R¹ is —C(O)R¹⁴.In some embodiments is a compound of Formula (IXa) wherein R¹ is—C(O)CH₃.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IXa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (IXa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IXa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆ alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (IXa) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (IXa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodimentof the aforementioned embodiments is a compound of Formula (IXa) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments is a compound of Formula (IXa) whereinR⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl.In a further embodiment of the aforementioned embodiments is a compoundof Formula (IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments is acompound of Formula (IXa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are ethyl.

In yet another aspect, provided herein is a compound having thestructure of Formula (X), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆ alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxyl, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₈cycloalkyl ring or an optionally substituted    C₂-C₉heterocycloalkyl ring;-   R⁶ and R⁷ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (X) wherein n is 0. Inanother embodiment is a compound of Formula (X) wherein n is 1. Inanother embodiment is a compound of Formula (X) wherein n is 2. Inanother embodiment is a compound of Formula (X) wherein n is 3. Inanother embodiment is a compound of Formula (X) wherein n is 4.

In another embodiment is a compound of Formula (X) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (X) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (X) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (X)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (X) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(X) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (X) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2,and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (X) whereinR³⁰ is optionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl),n is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (X) wherein R³⁰ is optionally substituted—(C₂-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (X) whereinR³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ isindependently halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (X) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (X)wherein R³⁰ is optionally substituted—O—(C₂-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (X) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (X) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (X) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (X) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈Cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (X) wherein R³⁰ is F, n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (X) wherein R³⁰ is F, n is 1 and R³¹ ishalogen. In another embodiment is a compound of Formula (X) wherein R³⁰is F, n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (X) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (X) wherein R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is F.

In another embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkyl amine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (X) wherein R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (X) wherein R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen.In another embodiment is a compound of Formula (X) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is F.

In another embodiment is a compound of Formula (X) wherein n is 0 andR³⁰ is halogen. In another embodiment is a compound of Formula (X)wherein n is 0 and R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In another embodiment is acompound of Formula (X) wherein n is 0 and R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl).

In another embodiment is a compound of Formula (X) wherein R⁴ and R⁵ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (X) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(X) wherein R⁴ and R⁵ are each hydrogen. In another embodiment is acompound of Formula (X) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment is a compoundof Formula (X) wherein R⁴ and R⁵ are each methyl. In another embodimentis a compound of Formula (X) wherein R⁴ and R⁵ together with the carbonatom to which they are attached, form an optionally substitutedC₃-C₈cycloalkyl ring or an optionally substituted C₂-C₉heterocycloalkylring.

In another embodiment is a compound of Formula (X) wherein R⁶ and R⁷ areeach independently selected from the group consisting of hydrogen,halogen, and optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (X) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(X) wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (X) whereinR⁶ and R⁷ are each methyl. In another embodiment is a compound ofFormula (X) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (X) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (X) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (X) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R⁸ is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (X) wherein R² is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R² isselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (X) wherein R² is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (X) wherein R² is methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (X) wherein R² is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (X) wherein R² is ethyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R² isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R² ishydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (X) wherein R¹ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted C₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments is acompound of Formula (X) wherein R¹ is halogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (X) whereinR¹ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R¹ is—OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of the aforementionedembodiments is a compound of Formula (X) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (X) wherein R¹ is—OR¹⁰ and R¹⁰ is methyl.

In yet another embodiment, provided herein is a compound having thestructure of Formula (Xa), or a pharmaceutically acceptable salt orsolvate thereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted aryl,    optionally substituted heteroaryl, and —C(O)R¹⁴;-   R⁸ is —C(O)OR²⁵ or —C(O)N(R²⁵)R²⁶;-   R¹⁴ is optionally substituted C₁-C₆alkyl:-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl;-   R³⁰ is halogen, optionally substituted    —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), or optionally substituted    —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl);-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkyl amine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl; and-   n is 0, 1, 2, 3, or 4.

In one embodiment is a compound of Formula (Xa) wherein n is 0. Inanother embodiment is a compound of Formula (Xa) wherein n is 1. Inanother embodiment is a compound of Formula (Xa) wherein n is 2. Inanother embodiment is a compound of Formula (Xa) wherein n is 3. Inanother embodiment is a compound of Formula (Xa) wherein n is 4.

In another embodiment is a compound of Formula (Xa) wherein n is 2 andeach R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (Xa) wherein n is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment is a compound of Formula (Xa) wherein n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (Xa)wherein n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ is F, nis 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkyl amine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (Xa) whereinR³⁰ is F, n is 2 and each R³¹ is independently halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment is a compound of Formula(Xa) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is F, n is 2 andeach R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2,and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment is a compound of Formula (Xa) whereinR³⁰ is optionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl),n is 2 and each R³¹ is halogen. In another embodiment is a compound ofFormula (Xa) wherein R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment is a compound of Formula (Xa) whereinR³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ isindependently halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and eachR³¹ is halogen. In another embodiment is a compound of Formula (Xa)wherein R³⁰ is optionally substituted—O—(C₂-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 2 and each R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein n is 1 andR³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (Xa) wherein n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Xa) wherein n is 1 and R³¹ is halogen. In anotherembodiment is a compound of Formula (Xa) wherein n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ is F, nis 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is F, n is 1 andR³¹ is halogen, or optionally substituted C₁-C₆alkyl. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is F, n is 1 andR³¹ is halogen. In another embodiment is a compound of Formula (Xa)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkyl amine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is optionallysubstituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ ishalogen, or optionally substituted C₁-C₆alkyl. In another embodiment isa compound of Formula (Xa) wherein R³⁰ is optionally substituted—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen. Inanother embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1and R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkyl amine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment is a compound of Formula (Xa) wherein R³⁰ is optionallysubstituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹is halogen, or optionally substituted C₁-C₆alkyl. In another embodimentis a compound of Formula (Xa) wherein R³⁰ is optionally substituted—O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is 1 and R³¹ is halogen.In another embodiment is a compound of Formula (Xa) wherein R³⁰ isoptionally substituted —O—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl), n is1 and R³¹ is F.

In another embodiment is a compound of Formula (Xa) wherein n is 0 andR³⁰ is halogen. In another embodiment is a compound of Formula (Xa)wherein n is 0 and R³⁰ is optionally substituted—(C₁-C₄alkylene)-(C₂-C₉heterocycloalkyl). In another embodiment is acompound of Formula (Xa) wherein n is 0 and R³⁰ is optionallysubstituted —O—(C₁-C₆alkylene)-(C₂-C₉heterocycloalkyl).

In some embodiments is a compound of Formula (Xa) wherein R¹ ishydrogen. In some embodiments is a compound of Formula (Xa) wherein R¹is halogen. In some embodiments is a compound of Formula (Xa) wherein R¹is optionally substituted C₁-C₆alkyl. In some embodiments is a compoundof Formula (Xa) wherein R¹ is unsubstituted C₁-C₆alkyl. In someembodiments is a compound of Formula (Xa) wherein R¹ is —CF₃. In someembodiments is a compound of Formula (Xa) wherein R¹ is —C(O)R¹⁴. Insome embodiments is a compound of Formula (Xa) wherein R¹ is —C(O)CH₃.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Xa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is hydrogen. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Xa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments isa compound of Formula (Xa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Xa) wherein R⁸ is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementioned embodimentsis a compound of Formula (Xa) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (Xa) wherein R⁸ is —C(O)N(R²⁵)R²⁶. In a further embodiment ofthe aforementioned embodiments is a compound of Formula (Xa) wherein R⁸is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodimentof the aforementioned embodiments is a compound of Formula (Xa) whereinR⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments is a compound of Formula (Xa) wherein R⁸ is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Xa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently unsubstituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments is a compound of Formula (Xa) wherein R⁸ is—C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ are methyl. In a furtherembodiment of the aforementioned embodiments is a compound of Formula(Xa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments is a compound ofFormula (Xa) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments is a compound selected from:

pharmaceutically acceptable salt, or pharmaceutically acceptable solvatethereof.

In some embodiments is a compound selected from:

a pharmaceutically acceptable salt, or pharmaceutically acceptablesolvate thereof.

In some embodiments, the therapeutic agent(s) (e.g. compound of Formula(I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII),(VIII), (IX), (IXa), (X), or (Xa)) is present in the pharmaceuticalcomposition as a pharmaceutically acceptable salt. In some embodiments,any compound described above is suitable for any method or compositiondescribed herein.

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns. In some embodiments, acompound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa) is used as asingle enantiomer. In some embodiments, a compound of Formula (I), (II),(III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa) is used as a racemic mixture.

The methods and formulations described herein include the use ofV-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structurespresented herein, as well as active metabolites of these compoundshaving the same type of activity.

In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein. Forexample, tautomers of a compound of Formula (III) may exist and areincluded in the scope of compounds of Formula (III) presented herein:

Similarly, tautomers of a compound of Formula (IV) may exist and areincluded in the scope of compounds of Formula (IV) presented herein:

Similarly, tautomers of a compound of Formula (V) may exist and areincluded in the scope of compounds of Formula (V) presented herein:

Similarly, tautomers of a compound of Formula (VI) may exist and areincluded in the scope of compounds of Formula (VI) presented herein:

Similarly, tautomers of a compound of Formula (IXa) may exist and areincluded in the scope of compounds of Formula (IXa) presented herein:

Similarly, tautomers of a compound of Formula (Xa) may exist and areincluded in the scope of compounds of Formula (Xa) presented herein:

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Incertain embodiments, upon in vivo administration, a prodrug ischemically converted to the biologically, pharmaceutically ortherapeutically active form of the compound. In certain embodiments, aprodrug is enzymatically metabolized by one or more steps or processesto the biologically, pharmaceutically or therapeutically active form ofthe compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (II), (III),(IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa),(X), or (Xa), as set forth herein are included within the scope of theclaims. In some cases, some of the herein-described compounds may be aprodrug for another derivative or active compound.

In specific embodiments, the compounds described herein exist insolvated forms with pharmaceutically acceptable solvents such as water,ethanol, and the like. In other embodiments, the compounds describedherein exist in unsolvated form.

In some embodiments, the compounds of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa) described herein include solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol.

In some embodiments, sites on the compounds of Formula (I), (II), (III),(IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa),(X), or (Xa) disclosed herein are susceptible to various metabolicreactions. Therefore incorporation of appropriate substituents at theplaces of metabolic reactions will reduce, minimize or eliminate themetabolic pathways. In specific embodiments, the appropriate substituentto decrease or eliminate the susceptibility of the aromatic ring tometabolic reactions is, by way of example only, a halogen, deuterium oran alkyl group.

In some embodiments, the compounds of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa) disclosed herein are isotopically-labeled, which are identical tothose recited in the various formulae and structures presented herein,but for the fact that one or more atoms are replaced by an atom havingan atomic mass or mass number different from the atomic mass or massnumber usually found in nature. In some embodiments, one or morehydrogen atoms are replaced with deuterium. In some embodiments,metabolic sites on the compounds described herein are deuterated. Insome embodiments, substitution with deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements.

In some embodiments, compounds described herein, such as compounds ofFormula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa),(VII), (VIII), (IX), (IXa), (X), or (Xa), are in various forms,including but not limited to, amorphous forms, milled forms andnano-particulate forms. In addition, compounds described herein includecrystalline forms, also known as polymorphs. Polymorphs include thedifferent crystal packing arrangements of the same elemental compositionof a compound. Polymorphs usually have different X-ray diffractionpatterns, melting points, density, hardness, crystal shape, opticalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UV-VIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen to provide stable moieties and compounds.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In other embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplemental (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following schemes.

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval.

Protective groups can be removed by acid, base, reducing conditions(such as, for example, hydrogenolysis), and/or oxidative conditions.Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilylare acid labile and may be used to protect carboxy and hydroxy reactivemoieties in the presence of amino groups protected with Cbz groups,which are removable by hydrogenolysis, and Fmoc groups, which are baselabile. Carboxylic acid and hydroxy reactive moieties may be blockedwith base labile groups such as, but not limited to, methyl, ethyl, andacetyl in the presence of amines blocked with acid labile groups such ast-butyl carbamate or with carbamates that are both acid and base stablebut hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, which include conversion to alkyl esters, or they may be blockedwith oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups may be blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pd⁰-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure).

Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood to which the claimedsubject matter belongs. In the event that there are a plurality ofdefinitions for terms herein, those in this section prevail. Allpatents, patent applications, publications and published nucleotide andamino acid sequences (e.g., sequences available in GenBank or otherdatabases) referred to herein are incorporated by reference. Wherereference is made to a URL or other such identifier or address, it isunderstood that such identifiers can change and particular informationon the internet can come and go, but equivalent information can be foundby searching the internet. Reference thereto evidences the availabilityand public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. In thisapplication, the use of “or” means “and/or” unless stated otherwise.Furthermore, use of the term “including” as well as other forms, such as“include”, “includes,” and “included,” is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definition of standard chemistry terms may be found in reference works,including but not limited to, Carey and Sundberg “Advanced OrganicChemistry 4^(th) Ed.” Vols. A (2000) and B (2001), Plenum Press, NewYork. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology.

Unless specific definitions are provided, the nomenclature employed inconnection with, and the laboratory procedures and techniques of,analytical chemistry, synthetic organic chemistry, and medicinal andpharmaceutical chemistry described herein are those recognized in thefield. Standard techniques can be used for chemical syntheses, chemicalanalyses, pharmaceutical preparation, formulation, and delivery, andtreatment of patients. Standard techniques can be used for recombinantDNA, oligonucleotide synthesis, and tissue culture and transformation(e.g., electroporation, lipofection). Reactions and purificationtechniques can be performed e.g., using kits of manufacturer'sspecifications or as commonly accomplished in the art or as describedherein. The foregoing techniques and procedures can be generallyperformed of conventional methods and as described in various generaland more specific references that are cited and discussed throughout thepresent specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods, compounds, compositions describedherein.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C_(j) . . . C₁-C_(x).C₁-C_(x) refers to the number of carbon atoms that make up the moiety towhich it designates (excluding optional substituents).

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroups may or may not include units of unsaturation. The alkyl moietymay be a “saturated alkyl” group, which means that it does not containany units of unsaturation (i.e. a carbon-carbon double bond or acarbon-carbon triple bond). The alkyl group may also be an “unsaturatedalkyl” moiety, which means that it contains at least one unit ofunsaturation. The alkyl moiety, whether saturated or unsaturated, may bebranched, straight chain, or cyclic.

The “alkyl” group may have 1 to 6 carbon atoms (whenever it appearsherein, a numerical range such as “1 to 6” refers to each integer in thegiven range; e.g., “1 to 6 carbon atoms” means that the alkyl group mayconsist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up toand including 6 carbon atoms, although the present definition alsocovers the occurrence of the term “alkyl” where no numerical range isdesignated). The alkyl group of the compounds described herein may bedesignated as “C₁-C₆ alkyl” or similar designations. By way of exampleonly, “C₁-C₆ alkyl” indicates that there are one to six carbon atoms inthe alkyl chain, i.e., the alkyl chain is selected from the groupconsisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, t-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, propen-3-yl(allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted.Depending on the structure, an alkyl group can be a monoradical or adiradical (i.e., an alkylene group).

An “alkoxy” refers to a “—O-alkyl” group, where alkyl is as definedherein.

The term “alkenyl” refers to a type of alkyl group in which two atoms ofthe alkyl group form a double bond that is not part of an aromaticgroup. Non-limiting examples of an alkenyl group include —CH═CH₂,—C(CH₃)═CH₂, —CH═CHCH₃, —CH═C(CH₃)₂ and —C(CH₃)═CHCH₃. The alkenylmoiety may be branched, straight chain, or cyclic (in which case, itwould also be known as a “cycloalkenyl” group). Alkenyl groups may have2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted.Depending on the structure, an alkenyl group can be a monoradical or adiradical (i.e., an alkenylene group).

The term “alkynyl” refers to a type of alkyl group in which the twoatoms of the alkyl group form a triple bond. Non-limiting examples of analkynyl group include —C≡CH, —C≡CCH₃, —C≡CCH₂CH₃ and —C≡CCH₂CH₂CH₃. The“R” portion of the alkynyl moiety may be branched, straight chain, orcyclic. An alkynyl group can have 2 to 6 carbons. Alkynyl groups can besubstituted or unsubstituted. Depending on the structure, an alkynylgroup can be a monoradical or a diradical (i.e., an alkynylene group).

“Amino” refers to a —NH₂ group.

The term “alkylamine” or “alkylamino” refers to the —N(alkyl)_(x)H_(y)group, where alkyl is as defined herein and x and y are selected fromthe group x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, takentogether with the nitrogen to which they are attached, can optionallyform a cyclic ring system. “Dialkylamino” refers to a —N(alkyl)₂ group,where alkyl is as defined herein.

The term “aromatic” refers to a planar ring having a delocalizedπ-electron system containing 4n+2π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, or morethan nine atoms. Aromatics can be optionally substituted. The term“aromatic” includes both aryl groups (e.g., phenyl, naphthalenyl) andheteroaryl groups (e.g., pyridinyl, quinolinyl).

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings can be formedby five, six, seven, eight, nine, or more than nine carbon atoms. Arylgroups can be optionally substituted. Examples of aryl groups include,but are not limited to phenyl, and naphthalenyl. Depending on thestructure, an aryl group can be a monoradical or a diradical (i.e., anarylene group).

“Carboxy” refers to —CO₂H. In some embodiments, carboxy moieties may bereplaced with a “carboxylic acid bioisostere”, which refers to afunctional group or moiety that exhibits similar physical and/orchemical properties as a carboxylic acid moiety. A carboxylic acidbioisostere has similar biological properties to that of a carboxylicacid group. A compound with a carboxylic acid moiety can have thecarboxylic acid moiety exchanged with a carboxylic acid bioisostere andhave similar physical and/or biological properties when compared to thecarboxylic acid-containing compound. For example, in one embodiment, acarboxylic acid bioisostere would ionize at physiological pH to roughlythe same extent as a carboxylic acid group. Examples of bioisosteres ofa carboxylic acid include, but are not limited to,

and the like.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. Cycloalkyls may be saturated, or partiallyunsaturated. Cycloalkyls may be fused with an aromatic ring (in whichcase the cycloalkyl is bonded through a non-aromatic ring carbon atom).Cycloalkyl groups include groups having from 3 to 10 ring atoms.Illustrative examples of cycloalkyl groups include, but are not limitedto, the following moieties:

and the like.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. Polycyclic heteroarylgroups may be fused or non-fused. Illustrative examples of heteroarylgroups include the following moieties:

and the like.

A “heterocycloalkyl” group or “heteroalicyclic” group refers to acycloalkyl group, wherein at least one skeletal ring atom is aheteroatom selected from nitrogen, oxygen and sulfur. The radicals maybe fused with an aryl or heteroaryl. Illustrative examples ofheterocycloalkyl groups, also referred to as non-aromatic heterocycles,include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Unless otherwise noted,heterocycloalkyls have from 2 to 10 carbons in the ring. It isunderstood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring).

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The term “haloalkyl” refers to an alkyl group that is substituted withone or more halogens. The halogens may the same or they may bedifferent. Non-limiting examples of haloalkyls include —CH₂Cl, —CF₃,—CHF₂, —CH₂CF₃, —CF₂CF₃, —CF(CH₃)₃, and the like.

The terms “fluoroalkyl” and “fluoroalkoxy” include alkyl and alkoxygroups, respectively, that are substituted with one or more fluorineatoms. Non-limiting examples of fluoroalkyls include —CF₃, —CHF₂, —CH₂F,—CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CF(CH₃)₃, and the like. Non-limitingexamples of fluoroalkoxy groups, include —OCF₃, —OCHF₂, —OCH₂F,—OCH₂CF₃, —OCF₂CF₃, —OCF₂CF₂CF₃, —OCF(CH₃)₂, and the like.

The term “heteroalkyl” refers to an alkyl radical where one or moreskeletal chain atoms is selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof.The heteroatom(s) may be placed at any interior position of theheteroalkyl group. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH₂—NH—OCH₃, —CH₂—O—Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. In addition, up to twoheteroatoms may be consecutive, such as, by way of example, —CH₂—NH—OCH₃and —CH₂—O—Si(CH₃)₃. Excluding the number of heteroatoms, a“heteroalkyl” may have from 1 to 6 carbon atoms.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

As used herein, the substituent “R” appearing by itself and without anumber designation refers to a substituent selected from among fromalkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon), and heterocycloalkyl.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heterocycloalkyl, —OH, alkoxy, aryloxy, alkylthio, arylthio,alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, —CN, alkyne,C₁-C₆alkylalkyne, halo, acyl, acyloxy, —CO₂H, —CO₂-alkyl, nitro,haloalkyl, fluoroalkyl, and amino, including mono- and di-substitutedamino groups (e.g. —NH₂, —NHR, —N(R)₂), and the protected derivativesthereof. In some embodiments, optional substituents are independentlyselected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH, —CO₂H,—CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂, —S(═O)₂NH₂,—S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl, fluoroalkyl,heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl,aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂, —OH,—NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In someembodiments, substituted groups are substituted with one or two of thepreceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic, saturated or unsaturatedcarbon atoms, excluding aromatic carbon atoms) includes oxo (═O).

The methods and formulations described herein include the use ofcrystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds having the structure of Formula (I), (II),(III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa), as well as active metabolites of these compoundshaving the same type of activity.

As used herein, the term “about” or “approximately” means within 20%,preferably within 10%, and more preferably within 5% of a given value orrange.

The term a “therapeutically effective amount” as used herein refers tothe amount of an FXR modulator that, when administered to a mammal inneed, is effective to at least partially ameliorate or to at leastpartially prevent diseases, disorders or conditions described herein.

As used herein, the term “expression” includes the process by whichpolynucleotides are transcribed into mRNA and translated into peptides,polypeptides, or proteins.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “FXR modulator” includes FXR agonists, antagonists and tissueselective FXR modulators, as well as other agents that induce theexpression and/or protein levels of FXR in cells.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human. Those skilled in the artrecognize that a therapy which reduces the severity of a pathology inone species of mammal is predictive of the effect of the therapy onanother species of mammal.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseasedisease or condition, preventing additional symptoms, inhibiting thedisease or condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions and Methods of Administration of FXRModulators

Administration of FXR modulators as described herein can be in anypharmacological form including a therapeutically effective amount of anFXR modulator alone or in combination with a pharmaceutically acceptablecarrier.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa) described herein,with other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. The pharmaceutical composition facilitates administration ofthe compound to an organism. In practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to amammal having a disease, disorder, or condition to be treated. In someembodiments, the mammal is a human. A therapeutically effective amountcan vary widely depending on the severity of the disease, the age andrelative health of the subject, the potency of the compound used andother factors. The compounds of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa)can be used singly or in combination with one or more therapeutic agentsas components of mixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include a compound of Formula (I), (II), (III), (IIIa), (IV),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa)described herein, can be formulated into any suitable dosage form,including but not limited to, aqueous oral dispersions, liquids, gels,syrups, elixirs, slurries, suspensions, aerosols, controlled releaseformulations, fast melt formulations, effervescent formulations,lyophilized formulations, tablets, powders, pills, dragees, capsules,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediaterelease and controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofthe FXR modulator and the particular therapeutic effect to be achievedand (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals. Thespecific dose can be readily calculated by one of ordinary skill in theart, e.g., according to the approximate body weight or body surface areaof the patient or the volume of body space to be occupied. The dose willalso be calculated dependent upon the particular route of administrationselected. Further refinement of the calculations necessary to determinethe appropriate dosage for treatment is routinely made by those ofordinary skill in the art. Such calculations can be made without undueexperimentation by one skilled in the art in light of the FXR modulatoractivities disclosed herein in assay preparations of target cells. Exactdosages are determined in conjunction with standard dose-responsestudies. It will be understood that the amount of the compositionactually administered will be determined by a practitioner, in the lightof the relevant circumstances including the condition or conditions tobe treated, the choice of composition to be administered, the age,weight, and response of the individual patient, the severity of thepatient's symptoms, and the chosen route of administration.

Toxicity and therapeutic efficacy of such FXR modulators can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, for example, for determining the LD₅₀ (the doselethal to 50% of the population) and the ED₅₀ (the dose therapeuticallyeffective in 50% of the population). The dose ratio between toxic andtherapeutic effects is the therapeutic index and it can be expressed asthe ratio LD₅₀/ED₅₀. FXR modulators that exhibit large therapeuticindices are preferred. While FXR modulators that exhibit toxic sideeffects may be used, care should be taken to design a delivery systemthat targets such modulators to the site of affected tissue in order tominimize potential damage to uninfected cells and, thereby, reduce sideeffects.

The data obtained from the cell culture assays and animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch FXR modulators lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any FXR modulatorused in a method described herein, the therapeutically effective dosecan be estimated initially from cell culture assays. A dose may beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (i.e., the concentration ofFXR modulator that achieves a half-maximal inhibition of symptoms) asdetermined in cell culture. Such information can be used to moreaccurately determine useful doses in humans. Levels in plasma may bemeasured, for example, by high performance liquid chromatography.

Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the modulation of FXR, or for the treatment of diseasesor conditions that would benefit, at least in part, from modulation ofFXR. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, or pharmaceutically acceptable solvate or hydrate thereof, intherapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from about 10%to about 100%, including, by way of example only, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, or about 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.01 mg per day to about 5000 mg per day, in some embodiments,about 1 mg per day to about 1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds described hereindescribed herein are from about 0.001 mg/kg to about 30 mg/kg. In oneembodiment, the daily dosages are from about 0.01 mg/kg to about 10mg/kg. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.1 mg to about 1000mg, conveniently administered in a single dose or in divided doses,including, but not limited to, up to four times a day or in extendedrelease form. Suitable unit dosage forms for oral administration includefrom about 1 to about 500 mg active ingredient. In one embodiment, theunit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about500 mg. The foregoing ranges are merely suggestive, as the number ofvariables in regard to an individual treatment regime is large, andconsiderable excursions from these recommended values are not uncommon.Such dosages may be altered depending on a number of variables, notlimited to the activity of the compound used, the disease or conditionto be treated, the mode of administration, the requirements of theindividual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

EXAMPLES

The following examples are offered for purposes of illustration, and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Example 1: Synthesis of (E)-isopropyl6-(3,4-difluorobenzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(12)

Step 1: A solution of hydrazine hydrate (34.4 g, 0.687 mol, 1.1 eq) inethanol (400 mL) was added to a solution of compound 1 (150 g, 0.62 mol)in ethanol (1000 mL) at 0° C. The reaction was allowed to warm to roomtemperature and stirred for 24 hr. The reaction was concentrated invacuo, dissolved in ethyl acetate (2000 mL), washed with 5% citric acid(2000 mL), sat'd NaHCO₃ (2000 mL) and brine, dried (MgSO₄), andconcentrated in vacuo to afford a light yellow solid, compound 2 (113 g,88%).

Step 2: To a solution of compound 2 (20.0 g, 96.1 mmol) in acetic acid(200 mL) was added sodium acetate (23.6 g, 288.3 mmol, 3.0 eq.). To thesuspended solution was added Br₂ (14.7 mL, 288.3 mmol, 3.0 eq.)dropwise. The resulting mixture was stirred at room temperature for 10minutes, and then heated at 100° C. in a sealed-tube for 5 hr. Thesolvent and Br₂ was removed in vacuo. The residue was diluted with ethylacetate (600 mL), washed with water (2×600 mL), saturated NaHCO₃ (600mL), and brine. The organic phase was dried over MgSO₄, and concentratedin vacuo. The crude product was purified by column chromatography (SiO₂,DCM/EA=9/1) to afford an ivory solid 3 (20 g×2 batch; 51.4 g, 188.3 mol,98%).

Step 3: A solution of compound 3 (96.5 g, 353.4 mmol, 1.0 eq.) in dryTHF (1.2 L), and was cooled in an ice-water bath. MeMgBr (471 mL, 3M inether solution, 1.41 mol, 4.0 eq.) was added dropwise. The resultingmixture was stirred at 0° C. for 30 minutes, then room temperatureovernight. The reaction was cooled to 0° C., then quenched withsaturated NH₄Cl solution (1.6 L). The organic phase was washed withbrine, and dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (SiO₂, DCM/EA=9/1) toafford an ivory solid 4 (69.1 g, 253.2 mmol, 72%).

Step 4: To a suspension of indium(III) bromide (6.5 g, 18.3 mmol, 0.1eq.) in dichloromethane (500 mL) was added trimethylsilyl cyanide (69mL, 549.4 mmol, 3.0 eq.). To this mixture, at room temperature, wasadded dropwise compound 4 (50.0 g, 183.1 mmol, 1.0 eq.) indichloromethane (1500 mL). The resulting mixture was stirred at roomtemperature overnight. Saturated NaHCO₃ was added and the mixture wasfiltered through a celite pad. The filtrate was partitioned betweensaturated NaHCO₃ and dichloromethane and the aqueous layer was extractedone more time with ethyl acetate. The combined organic layers were driedover MgSO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (SiO₂, DCM to DCM/MeOH=30/1) to afford a brown oil5 (50 g×2 batch; 107.1 g).

Step 5: To a solution of compound 5 (56.3 g, 199.7 mmol, 1.0 eq.) inCH₃CN (1600 mL), was added K₂CO₃ (82.8 g, 599.1 mmol, 3.0 eq.) and PMBCl(32.5 mL, 239.6 mmol, 1.2 eq.). The mixture was heated at reflux for 2hr. The reaction was cooled to room temperature. The inorganic solid wasremoved by filtration, and the mother liquid was concentrated in vacuo.The crude product was purified by column chromatography (SiO₂,Hex/EA=9/1) to afford a yellow oil 6 (56.3 g, 50.8 g×2 batch, 133.5 g,332.0 mmol, 91%).

Step 6A: To a suspension of zinc dust (4.1 g, 31.0 mmol, 2.0 eq.) in dryether (40 mL) was added dropwise HCl (2M solution in ether; 2 mL, 0.13eq.). The suspension was heated to reflux, and isopropyl bromoacetate (4mL, 31.0 mmol, 2.5 eq.) was added dropwise. The solution was stirred atthis temperature for 4 hr and cooled to room temperature.

Step 6B: To a solution of 6 ((5.0 g, 12.4 mmol, 1.0 eq.) in anhydrousTHF (100 mL) was added Pd(P(tBu)₃)₂ (5.1 g, 9.94 mmol, 0.8 eq.) underargon. The solution of (2-isopropoxy-2-oxoethyl) zinc bromide from step6A was added drop-wise. The resulting mixture was stirred in an oil bathwith heating from room temperature to 75° C. within 10 minutes. Thereaction mixture was heated at 75° C. for 2 hr. The reaction mixture wascooled to room temperature and quenched with saturated NH₄Cl (200 mL).After extraction of the product with ethyl acetate, the crude productwas purified by column chromatography (SiO₂, Hex/EA=9/1→Hex/EA=6/1) toafford an ivory oil 7 (2.4 g, 5.7 mmol, 46%).

Step 7: To a solution of compound 7 (7.8 g, 18.42 mmol, 1.0 eq) in THF(80 mL) and iPrOH (160 mL) was added Boc anhydride (8.04 g, 36.84 mmol,2.0 eq) and a Ra—Ni slurry in water (40 mL). The resulting mixture washydrogenated at H₂ 40 psi for 4 h. The catalyst was carefully removed byfiltration. The filtrate was concentrated in vacuo. The crude productwas purified by column chromatography (SiO₂, HX/EA=5/1) to afford asticky oil 8 (6.9 g, 71%).

Step 8: Compound 8 (6.9 g, 13.08 mmol) was dissolved in Bredereck'sreagent (55 mL). The solution was flushed with nitrogen, and then heatedat 115° C. in a sealed tube for 3 h. The mixture was diluted with CH₂Cl₂(500 mL). The organic phase was washed with water and brine, dried overMgSO₄, filtered and concentrated. The crude mixture was purified bycolumn chromatography (SiO₂, Hx/EA=2/1) to afford a sticky oil 9 (6.8 g,89%).

Step 9A: To a solution of compound 9 (6.8 g, 11.67 mmol) in dry CH₂Cl₂(50 mL) was added TFA (30 mL). The solution was stirred at roomtemperature for 15 minutes. The solvent was removed in vacuo. Theresidue was diluted with CH₂Cl₂ (500 mL), washed with saturated NaHCO₃and brine, dried over MgSO₄, filtered and concentrated to afford thefree amine intermediate.

Step 9B: To a solution of the intermediate from step 9A in iPrOH (100mL) was added concentrated HCl in water (3.4 mL). The resulting mixturewas heated at 100° C. in a sealed tube for 18 h. The solvent was removedin vacuo. The residue was dissolved in CH₂Cl₂ (500 mL), washed withsaturated NaHCO₃ and brine, dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography (SiO₂,Hx/EA=2/1) to afford solid 10 (3.7 g, 72%).

Step 10: To a solution of 10 (2 g, 4.57 mmol) in dry THF (50 mL) wasadded LiHMDS (1M in hexane, 6.85 mL, 1.5 eq) drowise at 0° C.3,4-difluorobenzoyl chloride (1.15 mL, 2.0 eq) was then added dropwise.The resulting mixture was stirred at room temperature for 2 h. Themixture was quenched with saturated NH₄Cl and extracted with ethylacetate. The organic solution was dried over MgSO₄, filtered andconcentrated. The crude product was purified by column chromatography(SiO₂, Hx/EA=5/1) to afford solid 11 (2 g, 75%).

Step 11: A solution of compound 11 (2 g, 3.46 mmol) in TFA (20 mL) washeated at 90° C. in a sealed tube for 10 minutes. The TFA was removed invacuo and the crude product was purified by column chromatography (SiO₂,DCM/Hx/EA=10/20/0.5) to afford the title compound 12 (1.3 g, 82%). LCMSm/z 444.1 [M+H]⁺.

Example 2: Synthesis of (E)-ethyl6-(3,4-difluorobenzoyl)-3,4,4-trimethyl-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(23)

Step 1: Methyl 3-oxobutanoate (8 g, 1.0 eq.) and1,1-dimethoxy-N,N-dimethylmethanamine (DMFDMA) (9.8 g, 1.2 eq.) werecombined in a 100 mL flask. The mixture was heated at 100° C. for 4 h.The mixture was cooled to room temperature and diluted with EtOH (40mL). To this solution was added dropwise hydrazine hydrate (4.2 g, 1.2eq). The resulting mixture was heated at refluxing overnight. Thesolvent was removed in vacuo. The residue was dissolved in ethyl acetate(50 mL), washed with water (3×30 mL) and brine, and concentrated toafford crude compound 13 (8.6 g, 88%) which was used without furtherpurification.

Step 2: To a solution of compound 13 (8.6 g, 1.0 eq.) in acetic acid (50mL) was added sodium acetate (15.1 g, 3 eq.). To the suspended solutionwas added Br₂ (29.5 g, 3 eq.) dropwise. The resulting mixture wasstirred at room temperature for 10 minutes, and then heated at 100° C.in a sealed-tube for 3 h. The solvent and excess Br₂ was removed invacuo. The residue was diluted with ethyl acetate (100 mL), washed withwater (2×30 mL), saturated NaHCO₃, and brine. The organic phase wasdried over Na₂SO₄, and concentrated in vacuo to afford a yellow oil(13.5 g). The oil was dissolved in ethyl acetate (40 mL) and hexane (100mL) was added. The precipitated yellow solid was collected byfiltration, washed with hexane and dried to afford 14 (9.8 g, 72.8%)which was used without further purification.

Step 3: Compound 14 (5 g, 1.0 eq.), PMBCl (4.3 g, 1.2 eq.) and K₂CO₃(9.5 g, 3.0 eq.) were combined in dry CH₃CN (60 mL). The mixture washeated at reflux for 2 h. The reaction mixture was cooled to roomtemperature. The inorganic solid was removed by filtration and themother liquid was concentrated in vacuo. The crude oil was purified bycolumn chromatography to provide a mixture of 15 (6.9 g, 89%).

Step 4: A solution of 15 (1.5 g, 1.0 eq.) in dry THF (20 mL) under N₂was cooled with an ice-water bath. MeMgBr (5.9 mL, 3M in ether solution,4.0 eq.) was added dropwise. The resulting mixture was stirred at 0° C.for 30 min, and then at room temperature for 4 h. The reaction wascooled to 0° C., and quenched with saturated NH₄Cl (20 mL). The mixturewas extracted with ethyl acetate (2×40 mL). The organic phase was washedwith brine, and dried over Na₂SO₄. The crude mixture was purified bycolumn chromatography to provide 16 (0.72 g, 48%).

Step 5: To a solution of compound 16 (0.7 g, 1.0 eq.) in dry CH₂Cl₂ (15mL) was added TMSCN (1.02 g, 5.0 eq.). The mixture was cooled to 0° C.under N₂. SnCl₄ (0.54 g, 1.0 eq.) was added to the reaction solutiondropwise over 5 minutes. The resulting mixture was stirred at roomtemperature for 4 h. The reaction was quenched by addition of ice-water(20 mL), and then washed with KF aqueous solution and brine. The crudemixture was purified by column chromatography to afford 17 (0.57 g,79%).

Step 6: To a solution of compound 17 (0.5 g, 1.0 eq.) in dry THF (20 mL)was added Pd(P(tBu)₃)₂ (0.5 g). The mixture was flushed with nitrogenfor 2 minutes. A solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide inTHF (5.7 mL, ˜0.4M, 1.6 eq.) was added dropwise under N₂. The resultingmixture was stirred at 80° C. for 1 h. The reaction mixture was cooledto room temperature and quenched with saturated NH₄Cl (30 mL). The crudemixture was purified by column chromatography to provide 18 (0.33 g,65%).

Step 7: To a mixture of compound 18 (0.33 g, 1.0 eq.) in THF (10 mL) andEtOH (10 mL) was added Boc anhydride (0.3 g, 1.5 eq.), and Ra—Ni inwater (8 mL). The resulting mixture was hydrogenated at H₂ 40 psi for 6h. The catalyst was carefully removed by filtration. The solvent wasconcentrated in vacuo. The crude mixture was purified by columnchromatography directly to give 19 (0.38 g, 90%).

Step 8: Compound 19 (380 mg) was dissolved in1-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (3 mL). The solutionwas flushed with nitrogen, and then heated at 115° C. in a sealed-tubefor 1.5 h. The mixture was diluted with CH₂Cl₂ (50 mL), washed withwater and brine. The crude mixture was purified by column chromatographyto give a mixture of 20 (370 mg, 87%).

Step 9: A solution of compound 20 (370 mg) in TFA (4 mL) was stirred atroom temperature overnight. TFA was removed in vacuo. The residue wasdissolved in CH₂Cl₂ (40 mL), washed with saturated NaHCO₃ and brine. Thesolvent was concentrated in high vacuo to afford 21 (244 mg, 92%).

Step 10: Compound 21 (65 mg, 1.0 eq) and DIEA (70 mg, 3.0 eq) weredissolved in CH₂Cl₂ (5 mL). To the solution was added3,4-difluorobenzoyl chloride (78 mg, 2.5 eq). The resulting mixture wasstirred at room temperature for overnight. The mixture was washed withsaturated NaHCO₃ and brine. The crude mixture was purified by columnchromatography to provide 22 (62 mg, 69%).

Step 11: A solution of 22 (60 mg) in TFA (2 mL) and anisole (0.2 mL) washeated at 150° C. in a sealed-tube for 40 min. The TFA and anisole wereremoved in vacuo. The residue was purified by column chromatographydirectly to afford the title compound 23 (39 mg, 85%) as a white solid.LCMS m/z 390.3 [M+H]⁺.

Example 3: Synthesis of (E)-ethyl6-(3,4-difluorobenzoyl)-3-(4-fluorophenyl)-4,4-dimethyl-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(39)

Step 1: A mixture of ethyl 3-bromo-1H-pyrazole-4-carboxylate (5.0 g, 1.0eq.) in 2-methylpropan-2-ol (15 mL) was stirred at 30° C. for 10 minutesto form a clear solution. To the solution was added concentratedsulfuric acid (2.2 mL, 1.02 eq.) dropwise. The resulting mixture washeated at reflux for 3 h. The reaction mixture was cooled to roomtemperature, and diluted with ethyl acetate (50 mL). The organic phasewas washed with water and brine, and dried over Na₂SO₄. The solvent wasconcentrated in high vacuo to afford a light brown solid 24 (6.1 g, 98%)which was used without further purification.

Step 2: A solution of 24 (5.0 g, 1.0 eq.) in dry THF (80 mL) was cooledto −78° C. under N₂. LAH powder (1.0 g, 1.5 eq.) was added. Theresulting mixture was stirred at −78° C. for 5 min, and then graduallywarmed to 0° C. in 2 h. The reaction was stirred at 0° C. for 1 hr. Thereaction was carefully quenched by adding water (5 mL), and then addedNa₂SO₄ was added. The inorganic salt was removed by filtration. Thecrude mixture was purified on silica gel column to provide 25 (2.2 g,52%).

Step 3: To a solution of 25 (1.0 g) in CH₂Cl₂ (10 mL) was added SOCl₂ (3mL). The resulting mixture was stirred at room temperature for 6 h. Thesolvent and excess SOCl₂ was removed in vacuo to provide 26 (1.1 g)which was used without purification.

Step 4: To a solution of 26 (1.1 g, 1.0 eq) in DMSO (20 mL) was addedKCN (1.1 g, 4.0 eq). The mixture was stirred at 40° C. overnight. Thereaction mixture was diluted with ethyl acetate (100 mL), washed withwater (3×50 mL) and brine. The solvent was removed in vacuo and theresidue was purified by column chromatography to afford 27 (0.75 g,72%).

Step 5: To a solution of 27 (0.75 g, 1.0 eq.) in dry THF (25 mL) underN₂ at 0° C. was added NaH (0.27 g, 2.2 eq., 60% in mineral oil). Themixture was stirred at 0° C. for 30 min, and then CH₃I (1.1 g, 2.5 eq.)was added. The resulting mixture was stirred at 0° C. for 3 h, and thenat room temperature overnight. The reaction was quenched by addingsaturated NH₄Cl, and extracted with ethyl acetate (2×50 mL). The solventwas removed in vacuo and the residue was purified by columnchromatography to afford 28 (0.65 g, 78%).

Step 6: To a solution of compound 28 (250 mg, 1.0 eq.) and(4-fluorophenyl)boronic acid (156 mg, 1.2 eq.) in 1,4-dioxane (15 mL),was added 2M K₂CO₃ in water (2 mL). The mixture was flushed with N₂, andthen added PdCl2(dppf) (38 mg, 0.05 eq.) was added. The resultingmixture was heated at 90° C. overnight. The reaction mixture was dilutedwith ethyl acetate (50 mL), and washed with water and brine. The solventwas removed in vacuo and the residue was purified by columnchromatography to provide 29 (217 mg, 82%).

Step 7: A solution of 29 (150 mg) in TFA (2 mL) and anisole (0.4 mL) washeated at 150° C. in a sealed-tube for 1 h. The TFA and anisole wereremoved in vacuo, and the residue was purified by column chromatographyto afford 30 (85 mg, 65%).

Step 8: To a solution of compound 30 (1.5 g) and pyridine (10 mL) in dryTHF (50 mL) was added SOCl₂ (5 mL) at 0° C. The resulting mixture washeated at 75° C. in for 2 h. The reaction mixture was concentrated invacuo, the residue was suspended in ice-water (100 mL) and extractedwith ethyl acetate (3×40 mL). The combined organic phase was washed withsaturated NaHCO₃ (2×50 mL) and brine. The solvent was removed in vacuoand the residue was purified on silica-gel to afford 31 (1.0 g, 72%).

Step 9: A solution of compound 31 (1.0 g, 1.0 eq.) in acetic acid (50mL) was added sodium acetate (0.894 g, 2.5 eq.). To the suspendedsolution was added Br₂ (1.74 g, 2.5 eq.) dropwise. The resulting mixturewas stirred at room temperature for 10 minutes, and then heated at 100°C. in a sealed-tube for 3 h. The solvent and excess Br₂ was removed invacuo. The residue was diluted with ethyl acetate (60 mL), washed withwater (2×30 mL), saturated NaHCO₃, and brine. The solvent was removed invacuo and the residue was purified on silica-gel column to provide 32(0.8 g, 60%).

Step 10: Compound 32 (800 mg, 1.0 eq.), PMBCl (488 mg, 1.2 eq.) andK₂CO₃ (1.08 g, 3.0 eq.) were combined in dry CH₃CN (80 mL). The reactionmixture was heated at reflux for 2 h. The reaction mixture was cooled toroom temperature. The inorganic solid was removed by filtration and themother liquid was concentrated in vacuo. The crude oil was purified bycolumn chromatography to provide a mixture of 33A and 33B (998 mg, 90%).

Step 11: To a solution of 33A and 33B (550 mg, 1.0 eq.) in dry THF (40mL) was added Pd(P(tBu)₃)₂ (550 mg). The mixture was flushed with N₂ for2 min. A solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide in THF (5.1mL, ˜0.4M, 1.6 eq.) was added dropwise under N₂. The resulting mixturewas stirred at 80° C. for 1 h. The reaction mixture was cooled to roomtemperature and quenched with saturated NH₄Cl (30 mL). The solvent wasremoved in vacuo and the residue was purified by column chromatographyto provide a mixture of 34A and 34B (280 mg, 50%).

Step 12: To a solution of 34A and 34B (280 mg, 1.0 eq.) in THF (15 mL)and EtOH (15 mL) was added Boc anhydride (280 mg, 2.0 eq.) and Ra—Ni (5mL). The resulting mixture was hydrogenated at H₂ 40 psi for 4 h. Thecatalyst was carefully removed by filtration. The solvent wasconcentrated in vacuo. The crude mixture was purified by columnchromatography to give a mixture of 35A and 35B (220 mg, 63%).

Step 13: A solution of 35A and 35B (220 mg) inl-tert-butoxy-N,N,N′,N′-tetramethylmethanediamine (3 mL) was flushedwith nitrogen, and then heated at 115° C. in a sealed-tube for 1.5 h.The reaction mixture was diluted with CH₂Cl₂ (50 mL), washed with waterand brine. The solvent was removed in vacuo and the residue was purifiedby column chromatography to give 36A (60 mg) and 36B (110 mg).

Step 14: A solution of 36B (110 mg) in TFA (1.5 mL) and CH₂Cl₂ (1.5 mL)was stirred at room temperature overnight. Volatiles were removed invacuo. The residue was dissolved in CH₂Cl₂ (40 mL), washed withsaturated NaHCO₃, and brine. The solvent was concentrated in high vacuoto afford 37 (80 mg, 96%).

Step 15: To a solution of 37 (80 mg, 1.0 eq) and DIEA (69 mg, 3.0 eq) inCH₂Cl₂ (8 mL) was added 3,4-difluorobenzoyl chloride (70 mg, 2.2 eq).The resulting mixture was stirred at room temperature overnight. Themixture was washed with saturated NaHCO₃ and brine. The solvent wasremoved in vacuo and the residue was purified by column chromatographyto provide 38 (68.4 mg, 65.5%).

Step 16: A solution of 39 (60 mg) in TFA (2 mL) and anisole (0.2 mL) washeated at 150° C. in a sealed-tube for 45 minutes. The TFA and anisolewere removed in vacuo. The residue was purified by column chromatographyto afford the title compound 39 (29 mg, 60%) as a white solid. LCMS m/z470.4 [M+H]⁺.

Example 4: Synthesis of (E)-ethyl6-(3,4-difluorobenzoyl)-4,4-dimethyl-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(45)

Step 1: To a solution of 28 (0.5 g, 1.0 eq.) in dry THF (25 mL) wasadded Pd(P(tBu)₃)₂ (0.5 g). The mixture was flushed with N₂ for 2minutes. A solution of (2-ethoxy-2-oxoethyl)zinc(II) bromide in THF(11.6 mL, ˜0.4M, 2.5 eq.) was added dropwise under N₂. The resultingmixture was stirred at 80° C. for 1 h. The reaction mixture was cooledto room temperature and quenched with saturated NH₄Cl (30 mL). Thesolvent was removed in vacuo and the residue was purified by columnchromatography to provide 40 (0.28 g, 55%).

Step 2: To a mixture of 40 (0.28 g, 1.0 eq.) in THF (10 mL) and EtOH (10mL) was added Boc anhydride (0.44 g, 2.0 eq.), 5 mL Ra—Ni in water and afew drops of saturated NH₄OH. The resulting mixture was hydrogenated atH₂ 40 psi for 3 h. The catalyst was carefully removed by filtration. Thesolvent was concentrated in vacuo. The crude mixture was by columnchromatography to give 41 (0.35 g, 92%).

Step 3: A solution of 41 (350 mg) in DMFDMA (3 mL) was heated at 150° C.in a microwave reactor for 10 h. The excess DMFDMA was removed in highvacuo. The crude mixture was purified by column chromatography to afford42 (128 mg, 32%).

Step 4: A solution of 42 (128 mg) in TFA (2 mL) was stirred at roomtemperature overnight. TFA was removed in vacuo. The residue wasdissolved in CH₂Cl₂ (40 mL), and washed with saturated NaHCO₃ and brine.The solvent was removed under high vacuo to afford 43 μl mg, 90%).

Step 5: To a solution of 43 (60 mg, 1.0 eq) and DIEA (80 mg, 3.0 eq) inCH₂Cl₂ (5 mL) was added 3,4-difluorobenzoyl chloride (91 mg, 2.5 eq).The resulting mixture was stirred at room temperature overnight. Themixture was washed with saturated NaHCO₃ and brine. The solvent wasremoved in vacuo and the residue was purified by column chromatographyto provide 44 (58 mg, 65%).

Step 6: A solution of compound 44 (40 mg) in 2 mL formic acid was heatedat 150° C. in a microwave reactor for 1 h. The formic acid was removedin vacuo. The crude mixture was purified by column chromatography toprovide the title compound 45 (11 mg, 32%). LCMS m/z 316.2 [M+H]⁺.

Examples 5-49

The compounds in the table below were synthesized as described in theprevious examples using the appropriate starting materials.

LCMS Ex. Structure m/z 5

418.1 6

569.3 7

551.5 8

550.5 9

565.7 10

432.6 11

492.6 12

539.3 13

551.5 14

457.6 15

474.4 16

458.4 17

440.5 18

397.2 19

397.3 20

397.2 21

465.4 22

444.5 23

440.4 24

458.5 25

428.3 26

446.4 27

430.4 28

448.4 29

419.4 30

416.6 31

446.4 32

418.4 33

428.3 34

405.4 35

402.4 36

404.4 37

414.5 38

432.4 39

432.3 40

418.3 41

404.2 42

422.1 43

390.1 44

396.3 45

389.3 46

390.1 47

420.2 48

346.3 49

358.1

Example 50: FXR Agonist Assay

Starting from 3.33 mM of compound in DMSO solution, a 10-point 3-foldserial dilution was made by diluting 5 μL of compound into 10 μL ofDMSO. The serially diluted compound was then diluted 1:33 into DMEM.This medium was then diluted ten-fold into the culture medium with thecells (10 μL/well). All concentration points are assayed in duplicate.Plates were incubated at 37° C. for 20 hours. After the incubation, 20μL of culture medium were removed from each well and mixed with 50 μL ofassay solution (Pierce™ Gaussia Luciferase Flash Assay Kit). Theluminescence was measured immediately after addition of the Lucsubstrate with an Envision microplate reader. The raw data was uploadedto CDD and dose-response curves were generated using theLevenberg-Marquardt algorithm integrated into CDD. A negative controlDMSO is included on each plate and used to normalize the data with theCDD built-in normalization function. The EC50 data for the assay isshown in Table 1.

TABLE 1 Example FXR EC50 (nM) 1 A 2 A 3 A 4 B 5 A 6 B 7 B 8 A 9 A 10 A11 A 12 A 13 A 14 A 15 A 16 A 17 A 18 B 19 C 20 B 21 B 22 B 23 A 24 A 25A 26 A 27 A 28 A 29 A 30 B 31 A 32 B 33 A 34 B 35 A 36 B 37 A 38 A 39 A40 A 41 A 42 A 43 A 44 B 45 B 46 B 47 C 48 C 49 B A = EC₅₀ less than 200nM; B = EC₅₀ greater than or equal to 200 nM and less than 1 μM; C =EC₅₀ greater than or equal to 1 μM and less than 10 μM.

Example 51: Phase 1 Study to Evaluate Safety of a Compound of Formula(I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII),(VIII), (IX), (IXa), (X), or (Xa) in Subjects with Non-AlcoholicSteatohepatitis (NASH) and Advanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a compound ofFormula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa),(VII), (VIII), (IX), (IXa), (X), or (Xa) when administered orally tosubjects with biopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of a compound of        Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI),        (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa);    -   The effects of 2 dose levels (25 mg and 50 mg) of a compound of        Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI),        (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa) on insulin        resistance and glucose homeostasis; and    -   Effects of a compound of Formula (I), (II), (III), (IIIa), (IV),        (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X),        or (Xa) on hepatocellular function as measured by assessment of        liver enzymes and biochemical markers of hepatic and metabolic        function and inflammation.

Patients: Eligible subjects will be men and women 18 years to 75 yearsof age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), for a compound of Formula (I), (II), (III),        (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII),        (IX), (IXa), (X), or (Xa) when administered intravenously to        subjects with biopsy-proven NASH with advanced liver fibrosis.        Specifically, this measure will be assessed by number of        subjects experiencing treatment emergent adverse events        indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to characterize the first-dose PK        profile of compound of Formula (I), (II), (III), (IIIa), (IV),        (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X),        or (Xa). The PK profile is assessed by the AUC (area under the        plasma concentration versus time curve) and Cmax (peak plasma        concentration) of a compound of Formula (I), (II), (III),        (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII),        (IX), (IXa), (X), or (Xa).    -   A secondary objective for the study is to characterize the PK        profile and serum level accumulation of a compound of Formula        (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa),        (VII), (VIII), (IX), (IXa), (X), or (Xa) following        administration of daily oral doses beginning 3 days after the        first dose.    -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

Arms Assigned Interventions Active Comparator: Cohort 1 Drug: Compoundof Formula Patient receives dose of compound of (I), (II), (III),(IIIa), (IV), (IVa), Formula (I), (II), (III), (IIIa), (IV), (V), (Va),(VI), (VIa), (VII), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX),(IXa), (X), or (Xa) (VIII), (IX), (IXa), (X), or (Xa) or Drug: Placeboplacebo Active Comparator: Cohort 2 Drug: Compound of Formula Patientreceives dose of compound of (I), (II), (III), (IIIa), (IV), (IVa),Formula (I), (II), (III), (IIIa), (IV), (V), (Va), (VI), (VIa), (VII),(IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa)(VIII), (IX), (IXa), (X), or (Xa) or Drug: Placebo Placebo ActiveComparator: Cohort 3 Drug: Compound of Formula Patient receives dose ofcompound of (I), (II), (III), (IIIa), (IV), (IVa), Formula (I), (II),(III), (IIIa), (IV), (V), (Va), (VI), (VIa), (VII), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa) (VIII), (IX),(IXa), (X), or (Xa) or Drug: Placebo placebo

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of a compoundof Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va), (VI),(VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa), in subjects withbiopsy-proven NASH with advanced fibrosis. This is a dose escalationdesign comprised of 3 sequential cohorts to evaluate the safety of acompound of Formula (I), (II), (III), (IIIa), (IV), (IVa), (V), (Va),(VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or (Xa) when administeredorally once a day for 7 weeks. Each cohort will consist of 8 subjects, 6randomized to receive a compound of Formula (I), (II), (III), (IIIa),(IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIII), (IX), (IXa), (X), or(Xa) and 2 randomized to receive placebo. Based on data safetymonitoring board (DSMB) and FDA review, 2 additional cohorts may beimplemented, consisting of 8 subjects.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

1-85. (canceled)
 86. A compound having the structure:

or a pharmaceutically acceptable salt thereof.
 87. The compoundaccording to claim 86 having the structure:


88. A pharmaceutical composition comprising a pharmaceuticallyacceptable diluent, excipient or binder, and a compound of claim 86; ora pharmaceutically acceptable salt thereof.
 89. A method of treating adisease, disorder or condition in a mammal that would benefit fromfarnesoid X receptor (FXR) agonism comprising administering to themammal a compound, or a pharmaceutically acceptable salt thereof,according to claim 86, wherein the disease, disorder or condition isselected from nonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis and obesity.
 90. Themethod of claim 89, wherein the disease, disorder or condition in amammal is nonalcoholic steatohepatitis (NASH).